Great progress has been made by evaluating the actions of exogenously applied opiates and opioid peptides in the CNS. What has been lacking, is concomitant progress concerning the neuronal effects elicited by the release of opioid peptides from endogenous stores. This seemingly subtle distinction concerning the effects of exogenously applied vs endogenously released opioids is actually one of primary importance when the clinically relevant issues of opioid tolerance and addiction are being considered. If the physiologic response to both acute, as well as chronic, opioid exposure are to be fully understood, the normal participation of the endogenous opioid system in neuronal function must be examined. This proposal investigates the neurophysiological effects of opioid receptor activation in the hippocampus, a brain region which expresses opioid binding sites and contains endogenous opioid peptides (dynorphins and enkephalins) in specific neuronal pathways. Extracellular and intracellular recordings from the in vitro hippocampal slice preparation will be used to investigate the synaptic actions of exogenously applied, and endogenously released opioids. The Schaffer collateral (SC)-CA1 pyramidal cell synapse of the hippocampal formation can undergo long-term potentiation (LTP) and, as recently demonstrated, long-tern depression (LTD), two potential cellular substrates of learning/memory processes. The GABAergic neurotransmitter system provides inhibitory input that regulates the activity of the principal neurons (pyrarnidal and granule cells) of the hippocampus, and thus can act to regulate synaptic plasticity. As exogenously applied opiates inhibit GABA release in the hippocampus, the working hypothesis of this proposal is that opioids can act as physiologically relevant GABA antagonists. Using electrophysiologic methods: l) the effects of GABA antagonists on LTD induction in the CA1 region will be evaluated to establish the GABAergic contribution to this specific plasticity phenomena, 2) Application of selective opioid agonists (mu, delta, kappa) will serve to determine the potential opioid involvement in modulating LTD induction, 3) Stimulation of the perforant path (which contains enkephalins) during the induction of LTD at the SC-CA1 synaPse will be employed to test the hypothesis that the induction of LTP and LTD is modulated by opioid peptides released from endogenous stores.